A quantitative understanding of the complexity of cellular metabolism integrated with tissue, organ, and whole-body processes requires sophisticated mathematical models, computer simulations, and validation with experimental data. Physiologically based models incorporate cellular metabolic reactions and transport processes of a large number of chemical species. In general, these dynamic models of spatially lumped and/or distributed systems involve highly nonlinear phenomena. Such models allow quantitative evaluation of metabolic pathways and regulatory mechanisms under normal and abnormal conditions in disease states. Consequently, these models can provide a basis for simulating the integrated effects of altering enzyme contents/activities or substrate concentrations with pharmacological agents. For this complex biomedical systems research, we propose a Center for Modeling integrated Metabolic Systems (MIMS). The thrust of the MIMS Center will be mathematical modeling and simulation of metabolic systems in response to stresses associated with hypoxia, exercise, and dietary inputs. A general integrative whole-body model will relate cellular to tissue metabolism in four major tissue-organ systems: skeletal muscle, brain, head, and liver. Biomedical research projects will incorporate one or more of the metabolic stresses in which the modeling can help quantify mechanisms and predict responses that cannot be directly measured. These projects will involve modeling of cell-tissue integration within an organ as well as modeling the integrated, whole-body effects of the combined tissue-organ systems. Critical experimental studies will be conducted for model validation. In addition to these project areas, the Center will have two cores that deal with modeling related research: Systems Modeling Integration and Computational Methods for Large Scale Dynamic Systems. Two other cores will support the missions of the MIMS Center: Web-Based Public information Site, and Research Training and Education. A partnership will be established between Case Western Reserve University, the primary site of the MIMS Center, and Cleveland State University, which has a substantial number of under-represented minorities in undergraduate programs.